Diethyl chlorophosphate → [5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]phosphoramidic acid diethyl ester

HRID 705567Notes

Reaction equation

HRID 705567 reaction equation
[F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[P:20](Cl)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1>[CH2:23]([O:22][P:20]([NH:17][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:4]=1)(=[O:21])[O:25][CH2:26][CH3:27])[CH3:24]

Participants

5

Reactant 3

HCID 13139Diethyl chlorophosphateHCID 24758Sodium hydrideHCID 578185745-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-amine

Product 1

HCID 57818673[5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]phosphoramidic acid diethyl esterYield 11%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a magnetically stirred solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.42 mmol) in dry THF (5 mL) under a nitrogen atmosphere was added NaH (0.017 g of a 60 wt. % suspension, 0.42 mmol) and the mixture was stirred until bubbling ceased. Diethyl chlorophosphate (0.073 g, 0.42 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was evaporated to dryness and the residue dissolved in EtOAc and washed saturated aqueous NH4Cl solution. The organic layer was separated, dried over Na2SO4, filtered, and evaporated. The crude material was purified on silica (acetone/CH2Cl2 gradient) to give 0.017 g (11%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]phosphoramidic acid diethyl ester as a white solid: mp 109-111° C.; 1H NMR (300 MHz, CDCl3) δ8.10 (t, J=1.8 Hz, 1H), 7.43 (m, 2H), 7.03 (t, J=8.5 Hz, 2H), 6.18 (br s, 1H), 5.35 (s, 2H), 4.25 (m, 4H), 1.38 (t, J=7.1 Hz, 6H); HPLC-MS (ESI) m/z 374 (M+H)+.

Workup

  1. customuntil bubbling
  2. stirringthe mixture was stirred at ambient temperature for 1 h
  3. customThe reaction mixture was evaporated to dryness
  4. dissolutionthe residue dissolved in EtOAc
  5. washwashed saturated aqueous NH4Cl solution
  6. customThe organic layer was separated
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. customevaporated
  10. customThe crude material was purified on silica (acetone/CH2Cl2 gradient)

Sources & evidence

ORD record
ord-c95193a27b6e426aab1a9e76d69ec52e
Source dataset
uspto-grants-2015_11
Patent number
US09174970B2

Reaction notes

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